The present invention is directed to the use of certain pyrido[1,2-a]-pyrazine derivatives, also described as bis-azabicyclic compounds, in the treatment of Parkinson""s disease, attention deficit hyperactivity disorder (xe2x80x9cADHDxe2x80x9d) and microadenomas in mammals, including humans. It is also directed to the use of a dopamine-2 (D2) receptor agonist in combination with a serotonin-1A (5HT1A) receptor agonist for the treatment for Parkinson""s Disease. It is also directed to the use of an alpha-2 (xcex12) adrenergic receptor ligand in combination with either a D2 receptor agonist or a 5HT1A receptor agonist for the treatment of ADHD. It is also directed to the use of a D2 receptor agonist in combination with a 5HT1A receptor agonist for the treatment of ADHD. It is also directed to the use of an alpha-2 (xcex12) adrenergic receptor ligand in combination with both a D2 receptor agonist and a 5HT1A receptor agonist for the treatment of ADHD.
Serotonin plays a role in several psychiatric disorders, including anxiety, Alzheimer""s disease, depression, nausea and vomiting, eating disorders, and migraine. (See Rasmussen et al., xe2x80x9cChapter 1. Recent Progress in Serotonin (5HT)1A Receptor Modulatorsxe2x80x9d, in Annual Reports in Medicinal Chemistry, Section I, 30, pp. 1-9, 1995, Academic Press, Inc.; Antigas et al., Trends Neurosci., 19 (9), 1996, pp. 378-383; and Wolf et al., Drug Development Research, 40, 1997, pp. 17-34.) Serotonin also plays a role in both the positive and negative symptoms of schizophrenia. (See Sharma et al., Psychiatric Annals., 26 (2), February, 1996, pp. 88-92.) Serotonin 1A receptor agonists have been shown to increase prefrontal cortex dopamine (DA) release. See Wedzony et al., Eur. J. Pharmacol., 305: 73-78 (1996). Buspirone, a 5HT1A receptor agonist, has been shown to be efficacious in treating a variety of symptoms associated with ADHD. Serotonin 1A receptor agonists have also been shown to reverse neuroleptic induced dystonia in nonhuman primates, a condition that mimics symptoms of human Parkinson""s disease. See Casey, D. E., Neuropsychopharmacol., 10:370S (1994).
Symptoms associated with ADHD have been shown to be relieved by catecholamine releasing drugs such as methylphenidate, and by postsynaptic xcex12 adrenergic receptor agonists such as clonidine. Also, presynaptic xcex12 adrenergic receptor antagonists have been shown to increase norepinephrine (NE) release.
A number of 1-(2-pyrimidinyl)-4-[4-(cyclic-imido)butyl]piperidine derivatives have been disclosed as anxiolytic agents which are generally lacking sedative activity. Among these are buspirone, where the cyclic-imido group is 4,4-tetramethylene-piperidine-2,6-dion-1-yl (Wu et al., U.S. Pat. Nos. 3,717,634 and 3,907,801); Casten et al., U.S. Pat. No. 4,182,763); gepirone, where the group is 4,4-dimethylpiperidine-2,6-dion-1-yl (Temple, Jr., U.S. Pat. No. 4,423,049); and ipsapirone, where the group is 1,1-dioxobenzo[d]isothiazol-3(2H)-on-yl (Dompert et al., German patent publication 3,321,969-A1). See also Ishizumi et al., U.S. Pat. Nos. 4,507,303 and 4,543,55; Freed et al., U.S. Pat. No. 4,562,255; Stack et al., U.S. Pat. No. 4,732,983; New et al., U.S. Pat. No. 4,524,026; and Stack, U.S. Pat. No. 4,788,290.
Compounds of the formula (I) below are disclosed in U.S. Pat. No. 5,122,525 as useful for the treatment of anxiety and depression. The use of such compounds for the treatment of addiction is described in U.S. Pat. No. 5,616,885.
This invention relates to a method of treating a disorder selected from Parkinson""s disease, ADHD, and microadenomas in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula: 
or a pharmaceutically acceptable acid addition salt thereof, wherein
X is N or CH;
Y is: 
SCH2, OCH2, Y1(CH2)n or Y1(CH2)n substituted on carbon with up to 2 methyl groups;
n is 1 or 2; and
Y1 is CH2, NH or NCH3;
that is effective in treating such disorder.
In the compounds of the formula (1), Y is preferably 
A particularly preferred compound is that wherein Z is Y1(CH2)n, Y1 is CH2, n is 1 and X is N.
The compounds of formula I are D2 receptor agonists and useful in the treatment of Parkinson""s disease. They also exhibit 5HT1A receptor agonist activity.
The compounds of formula I also exhibit activity as xcex12 adrenergic receptor antagonists and are useful in treatment of ADHD. The compounds increase hippocampal NE release and also increase prefrontal cortex DA release.
The compounds of the formula I that are basic can form acid addition salts with a variety of organic and inorganic acids. The acids that can be used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of the formula I are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The term xe2x80x9ctreatingxe2x80x9d as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
This invention also relates to a method for treating Parkinson""s Disease in a mammal, including a human, comprising administering to a mammal in need of such treatment a D2 receptor agonizing agent in combination with a 5HT1A receptor agonizing agent, wherein the two foregoing active agents are present in amounts such that the combination of such agents is effective in treating Parkinson""s Disease.
This invention also relates to a pharmaceutical composition for treating Parkinson""s disease in a mammal, including a human, comprising: (a) a D2 receptor agonizing agent or a pharmaceutically acceptable salt thereof; (b) a 5HT1A receptor agonizing agent or pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the foregoing two active agents are in the composition in amounts such that the combination of such agents is effective in treating Parkinson""s disease.
This invention also relates to a method of treating ADHD in a mammal, including a human, comprising administering to a mammal in need of such treatment an xcex12 adrenergic receptor ligand, or pharmaceutically acceptable salt thereof, in combination with either a D2 receptor agonizing agent or a 5HT1A receptor agonizing agent, or pharmaceutically acceptable salt thereof, wherein the foregoing two active agents are present in amounts such that the combination of such active agents is effective in treating ADHD.
This invention also relates to a pharmaceutical composition for treating ADHD in a mammal, including a human, comprising: (a) an xcex12 adrenergic receptor ligand or a pharmaceutically acceptable salt thereof; (b) a D2 receptor agonizing agent or a 5HT1A receptor agonizing agent, or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier, wherein the two foregoing active agents are present in the composition in amounts such that the combination of such agents is effective in treating ADHD.
This invention also relates to a method of treating ADHD in a mammal, including a human, comprising administering to a mammal in need of such treatment a D2 receptor agonizing agent, or pharmaceutically acceptable salt thereof, in combination with a 5HT1A receptor agonizing agent, or pharmaceutically acceptable salt thereof, wherein the foregoing two active agents are present in amounts such that the combination of such active agents is effective in treating ADHD.
This invention also relates to a pharmaceutical composition for treating ADHD in a mammal, including a human, comprising: (a) a D2 receptor agonizing agent or a pharmaceutically acceptable salt thereof; (b) a 5HT1A receptor agonizing agent or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the two foregoing active agents are present in the composition in amounts such that the combination of such agents is effective in treating ADHD.
This invention also relates to a method of treating ADHD in a mammal, including a human, comprising administering to a mammal in need of such treatment an xcex12 adrenergic receptor ligand, or pharmaceutically acceptable salt thereof, in combination with a D2 receptor agonizing agent, or pharmaceutically acceptable salt thereof, and also a 5HT1A receptor agonizing agent, or pharmaceutically acceptable salt thereof, wherein the three foregoing active agents are present in amounts such that the combination of such active agents is effective in treating ADHD.
This invention also relates to a pharmaceutical composition for treating ADHD in a mammal, including a human, comprising: (a) an xcex12 adrenergic receptor ligand or a pharmaceutically acceptable salt thereof; (b) a D2 receptor agonizing agent or a pharmaceutically acceptable salt thereof; (c) a 5HT1A receptor agonizing agent or a pharmaceutically acceptable salt thereof; and (d) a pharmaceutically acceptable carrier; wherein the foregoing three active agents are present in the composition in amounts such that the combination of such agents is effective in treating ADHD.
Compounds of the formula I may contain chiral centers and therefore may exist in different enantiomeric and diastereomic forms. The term xe2x80x9ccompounds of the formula Ixe2x80x9d, as used herein, refers to all optical isomers and all other stereoisomers of compounds of the formula I, as defined above, and to all racemic and other mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ such isomers or mixtures.
Formula I above includes compounds identical to those depicted but for the fact that one or more hydrogen or carbon atoms are replaced by isotopes thereof. Such compounds are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. Specific applications in research include radioligand binding assays, autoradiography studies and in vivo binding studies.
Examples of D2 receptor agonizing agents that can be used in the methods of this invention include, but are not limited to, compounds of the formula I and the pharmaceutically acceptable salts, pergolide, bromocriptane, ropinerol, and pramipexole.
Examples of 5HT1A receptor agonizing agents that can be used in the methods of this invention include, but are not limited to: (a) compounds of the formula I and their pharmaceutically acceptable salts, (b) buspirone (U.S. Pat. Nos. 3,717,638; 3,907,801 and 4,182,763); (c) gepirone (U.S. Pat. No. 4,423,049); (c) ipsapirone (German patent publication 3,321,969-A1); and (d) and flexinoxan.
Examples of xcex12 adrenergic receptor antagonizing agents that can be used in the methods of this invention include, but are not limited to, compounds of the formula I and their pharmaceutically acceptable salts, yohimbine and idazoxan.
Examples of more specific embodiments of this invention are the above methods of treating ADHD and pharmaceutical compositions for the treatment of ADHD that employ an xcex12 adrenergic receptor ligand wherein such ligand is a presynaptic xcex12 adrenergic receptor antagonist or a post synaptic xcex12 adrenergic receptor agonist.
A preferred method of this invention is a method of treating Parkinson""s Disease in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of the following compound of the formula I shown below: 
i.e., wherein X is nitrogen, wherein Y is a group of the formula 
(xe2x80x9csunipetronxe2x80x9d), or pharmaceutically acceptable salt thereof, that is effective in treating Parkinson""s Disease.
Another preferred embodiment of this invention is a method for treating ADHD in a mammal including a human, comprising administering to a mammal in need of such treatment an amount of sunipetron, or pharmaceutically acceptable salt thereof, that is effective in treating ADHD.
Another preferred method of this invention is a method for treating microadenomas in a mammal including a human, comprising administering to a mammal in need of such treatment an amount of sunipetron, or pharmaceutically acceptable salt thereof, that is effective in treating microadenomas.